Powder for delivery to the oral cavity

ABSTRACT

A powder for delivery to the oral cavity of a user is disclosed. The powder includes at least two populations of particles. A first population of particles includes a stimulant, and a second population of particles includes a flavorant. Also described is a cartridge containing the powder for use in an inhaler device and inhaler device containing the powder.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a National Phase entry of PCT Application No.PCT/GB2015/051870, filed on 26 Jun. 2015, which claims priority to GBPatent Application No. 1411526.5, filed on 27 Jun. 2014, which arehereby fully incorporated herein by reference.

TECHNICAL FIELD

The specification discloses a powder for delivery to the oral cavity ofa user.

BACKGROUND

Aerosol particles may be used to deliver substances to the oral cavityof a user.

SUMMARY

In accordance with a first aspect of the present disclosure, there isprovided a powder for delivery to the oral cavity of a user comprisingat least two populations of particles. A first population of particlescomprises a stimulant, and a second population of particles comprises aflavorant.

The powder may consist of three, four, five, or six populations ofparticles.

The sensations provided by the at least two populations of particles maydemonstrate different rates of perception and/or duration.

The mean particle size of one of the populations of particles may beless than 50% of the mean particle size of a different population ofparticles. One population of particles may have a mean particle size of7-350 μm, optionally 10-350 μm or 10-150 μm, and a different populationof particles may have a mean particle size of 350-750 μm, optionally450-750 μm.

The first population of particles may comprise a stimulant and a smallermean particle size, and the second population of particles may comprisea flavorant and a larger mean particle size. The stimulant may becapable of being perceived quickly by the user and taking effectrapidly, and the flavorant may be capable of being perceived later andpersisting for a longer duration.

At least one of the particle populations may comprise a tobacco extract.

The stimulant may comprise nicotine, caffeine, theophylline, ortheobromine.

The flavorant may comprise a sugar or sugar substitute, a sensationflavorant, a saliva stimulant, and/or a sensory modifier.

At least one of the powder populations may further comprise an enhancercomprising a bioadhesive, a pH modifier, a substance capable ofmodifying the electrostatic charge of particles, and/or a hydrophobicmaterial.

In some embodiments, the powder does not comprise a population ofparticles which consists, or consists essentially, only of sugar. Insome embodiments, the powder does not comprise a population of particleswhich consists, or consists essentially, only of gasified sugar.

At least one of the particle populations may comprise compositeparticles comprising an internal core and an external coating. Thecoating may comprise the stimulant or flavorant.

In accordance with a second aspect of the present disclosure, there isprovided a method of making a powder for delivery to the oral cavity.The method comprises separately preparing a first population ofparticles comprising a stimulant, and a second population of particlescomprising a flavorant, and then mixing the first and second populationstogether.

According to a third aspect of the disclosure, there is provided acartridge for an inhaler device, the cartridge containing a powder fordelivery to the oral cavity of a user, the powder comprising at leasttwo populations of particles, wherein a first population of particlescomprises a stimulant, and a second population of particles comprises aflavorant.

According to a fourth aspect of the disclosure, there is provided aninhaler device containing a powder for delivery to the oral cavity of auser, the powder comprising at least two populations of particles,wherein a first population of particles comprises a stimulant, and asecond population of particles comprises a flavorant.

In some embodiments, the inhaler of the fourth aspect may comprise acartridge of the third aspect.

Features described in relation to the first aspect may also apply to thesecond, third or fourth aspects of the disclosure.

DETAILED DESCRIPTION

The disclosed powders comprise at least two populations of particles andare intended to be delivered to the oral cavity of the user in order toimpart at least two different sensory experiences to the user.Specifically, the powders comprise at least a first particle populationcomprising a stimulant, and a second particle population comprising aflavorant.

The terms “oral cavity”, “buccal cavity”, and “mouth cavity” are usedinterchangeably and refer to the cavity lying at the upper end of thealimentary canal, bounded on the outside by the lips and inside by theoropharynx.

The particles may be delivered to the user's mouth by means of amechanism comprising entraining the particles in a flow of air, such asthat generated by user inhalation. However, the particles of the powdersare not delivered to the lungs to any substantial extent. Thissite-specific delivery is achieved primarily as a result of the size ofthe particles used. The powder particles are also generally not intendedfor sublingual delivery to the user.

In some embodiments, the powders may comprise three, four, five, or sixpopulations of particles. For example, the powders may consist of three,four, five, or six populations of particles. Generally, the powdersconsist of two populations of particles.

Particle Size

Various aspects of the sensation provided by the particle populations ofthe powder may be controlled as a function of the mean particle size ofthat particle population. For example, the magnitude, rate of onset, andduration of the sensation may all be adjusted by altering the meanparticle size of that particle population.

In some embodiments, at least two of the particle populations of thepowder may have different mean particle sizes. In these embodiments, thesensation associated with the particle population having a smaller meanparticle size may be perceived more rapidly, but for a shorter duration,than the sensation associated with the population which has a largermean particle size.

The mean particle size of one of the populations of particles may besubstantially less than the mean particle size of a different populationof particles within the powder. For example, the mean particle size ofone of the populations of particles may be less than 70%, 60%, 40%, or30% of the mean particle size of another population of particles.Generally, the mean particle size of one of the populations of particlesmay be less than about 50% of the mean particle size of a differentpopulation of particles within the powder.

In particular, a first population of particles may have a mean particlesize of 7-350 μm, 10-350 μm, such as less than about 325, 300, 275, or250 μm. In one embodiment, a first population of particles may have amean particle size of less than about 150 μm.

A second population of particles may have a mean particle size of350-750 μm, such as greater than about 375, 400, or 425 μm. In oneembodiment, a second population of particles may have a mean particlesize of greater than about 450 μm.

The particle size may also be important to control the delivery of thepowder. For example, particles that are smaller than about 7 μm or 10 μmmay be inhaled into the lower respiratory tract and airways of the lowerlung. For this reason, particles of the disclosed powder are generallylarger than about 7 μm or 10 μm in order to ensure that substantiallyall of the particles are delivered to the buccal cavity. For example,the powder particles may be larger than about 20, 30, 40, or 50 μm.Generally, in use at least 95, 98, or 99% of the particles are depositedin the oral cavity.

On the other hand, particles larger than about 750 μm may be associatedwith a gritty feel in the mouth which may be considered by some users tobe unpleasant. For this reason, particles of the disclosed powder aregenerally smaller than about 750 μm and may be smaller than 720 μm, 700μm, 650 μm, 600 μm, 550 μm or 500 μm.

Sensations

The disclosed powders comprise a first population of particlescomprising a stimulant, and a second population of particles comprisinga flavorant.

The sensations provided by the powder particles may be perceived by theuser through various mechanisms. For example, powder components such asflavorants may be perceived directly by receptors on the tongue and thewalls of the buccal cavity. Other powder components, such as stimulants,may be perceived by receptors elsewhere in the user's body aftercrossing the transmucosal surface.

Since the powders comprise solid particles, it will generally benecessary for the powder components to dissolve in the user's mouthbefore they can be perceived. In some cases, however, further reactionsmay be required. For example, the particles of one or more of thepopulations within the powder may comprise a coating which may need todissolve in order to expose the sensation-providing component. Inaddition, or alternatively, it may be necessary for components of thepowder to react together or to react with components of the user'ssaliva before the desired sensation can be perceived.

Various different types of sensation may be provided by at least two ofthe particle populations of the powder. For example, in someembodiments, the sensations may relate to the magnitude of theexperience perceived by the user, wherein the first and second particlepopulations may demonstrate different rates of perception and/orduration.

In addition, or alternatively, the sensations elicited by the particlepopulations may relate to the provision of a sensory experience, such asa stimulant effect, flavor, and/or other sensory modification.

The rate at which the sensation provided by a population of powderparticles is perceived by the user may vary considerably. For example,flavorants which are perceived by receptors in the mouth may provide theuser with an essentially instant flavor sensation. Generally, rapidlyperceived sensations such as these may be perceived by the user in lessthan 5, 3, 2, 1, or 0.5 seconds. Other sensations may be perceivedsignificantly more slowly. For example stimulants may need to cross thetransmucosal surface, accumulate in the blood, and act on receptorselsewhere in the body. Delayed sensations such as these may not beperceived by the user until at least 0.5, 1, 2, 5, or 10 minutes afterpowder delivery.

Moreover, the rate of perception of a sensation may be controlled andadjusted in various ways. For example, the sensation provided by smallerparticles may be perceived more rapidly than that provided by a powderin the form of larger particles. In addition, the particles may becoated to delay perception of a sensation, and the solubility of thecoating material may be adjusted to control the delay. In a furtherexample, the particles may comprise an excipient, the solubility ofwhich may regulate the release of the sensation providing component.Similar approaches may be used to control the duration over which asensation is perceived. Generally, the user may perceive a sensation forat least 5, 10, 15, or 30 seconds.

Thus, by means of the use of a plurality of different particlepopulations, a powder may be produced which delivers a plurality ofdifferent sensations, wherein each sensation may be perceived with adifferent rate of onset, and for a different duration.

Stimulant

One or more of the particle populations within the powder comprises astimulant.

The term “stimulant” refers to any substance that excites any bodilyfunction, and in particular substances that stimulate the brain andcentral nervous system, and a substance is considered to be a stimulantif it is capable of inducing alertness, elevated mood, wakefulness,increased speech, elevated motor activity, and/or decreased appetite.Sugars, including natural sugars such as lactose, glucose and sucrose,are not stimulants.

The stimulant may, for example, comprise nicotine, caffeine,theophylline, or theobromine, and preferably consists of nicotine orcaffeine. The terms “nicotine”, “caffeine”, “theophylline”, and“theobromine” include all active forms of these compounds. The stimulantmay be synthetically produced. Alternatively, the stimulant may beprovided in the form of an extract from a natural source, such astobacco, tea leaves, coffee beans, kola nuts, cocoa beans, guarana, orguayusa leaves.

In each usage of the powder, the user may consume one or a plurality ofindividual shots of powder. For example, in some embodiments, the powdermay be packaged such that each pack contains only a single shot ofpowder, and in this case, the level of stimulant in the powder may berelatively high. In other embodiments, the powder may be packaged suchthat each pack contains multiple shots, and in this case, the powder maybe arranged such that each shot contains a lower relative amount ofstimulant. Thus, the amount of stimulant delivered to the user in eachshot depends on the amount, frequency, and mode of delivery of thepowder, wherein the powder may comprise a greater stimulant content ifit is to be delivered in single shots with large intervals betweenshots. On the other hand, the stimulant content of the powder may belower if a large number of shots are intended to be consumed with a highfrequency. In general, when the powder comprises nicotine, the totalamount of nicotine delivered in each usage of the powder may be greaterthan about 0.01, 0.05, 0.1, 0.2, 0.3, or 0.4 mg, and less than about 5,4, 3, 2, or 1 mg, and may generally be, for example, between about0.1-1.5 mg. Likewise, when the powder comprises caffeine, the intendedtotal amount of caffeine delivered in each usage of the powder may begreater than about 10, 20, 50, 80, or 100 mg, and less than about 500,400, 300, or 250 mg, and may generally be, for example, between about50-400 mg.

Flavorant

One or more of the particle populations within the powder comprises aflavorant.

The terms “flavor” and “flavorant” refer to materials which, where localregulations permit, may be used to create a desired taste or aroma in aproduct for appropriately aged consumers. They may include for example,chocolate, coffee, wine, menthol, licorice, citrus, chamomile,fenugreek, clove, menthol, aniseed, cinnamon, cherry, berry, peach,apple, aniseed, Drambuie, bourbon, scotch, whiskey, spearmint,peppermint, lavender, honey, rose, vanilla, lemon, orange, cognac,jasmine, ginger. A single flavorant may be used, or by mixing existingflavorant, new flavors may be produced.

Generally, the flavorant may be produced from any food product,ingredient, or beverage. The flavorant may comprise imitation, syntheticor natural ingredients or blends thereof. Alternatively, the flavorantmay be provided in the form of an extract from a natural source.

Thus, a single extract from a natural source, for example a tobaccoextract, may comprise both a stimulant (in this example nicotine), and aflavorant (in this case tobacco-derived aromatic compounds and flavors).

One or more of the particle populations may comprise a component oftobacco, such as a tobacco extract and/or nicotine.

The flavorant may comprise a sugar and/or sugar substitute. The sugar orsugar substitute may comprise, for example, lactose, sucrose, glucose,fructose, sorbitol, or mannitol, a dihydrochalcone, monellin, a steviolglycoside, a dihydroflavonol, maltitol, sucralose, cyclamates, xylitol,a water-soluble artificial sweetener such as a soluble saccharin salt,acesulfame potassium, a dipeptide based sweetener such as an L-asparticacid derived sweetener or aspartame, a water-soluble sweetener such as achlorinated derivate of sucrose, for example chlorodeoxysucrose orchlorodeoxygalactosucrose; a protein based sweetener such as talin orthaumatin I or II, monatin, or a monatin derivative. In someembodiments, the flavorant may comprise saccharin.

Generally, the powder does not comprise a population of particles whichdoes not contain a stimulant or a flavorant, and consists, or consistsessentially, only of sugar. In some embodiments, the powder does notcomprise a population of particles which consists, or consistsessentially, only of gasified sugar.

The flavorant may comprise a sensation flavorant. The term “sensationflavorant” refers to a flavorant which provides a non-taste-specificorganoleptic effect to the oral cavity. For example, a sensationflavorant may provide a drying effect, a warming or cooling sensation,or may affect the trigeminal nerve, for example by causing a tingling orfizzing sensation.

The sensation flavorant may provide a heating effect, and may forexample, comprise capsaicin, dihydrocapsaicin, nordihydrocapsaicin,homodihydrocapsaicin, homocapsaicin, or nonivamide.

The sensation flavorant may provide a cooling effect, and may forexample, comprise menthol or mint (for example peppermint or spearmint),cyclic alpha-keto enamines, menthyl lactate, menthone glycerine acetal,menthoxypropanediol, isopulegol, paramenthan-3,8-diol, monomenthylsuccinate, monomenthyl glutarate, menthol ethylene glycol carbonate,menthol propylene glycol carbonate, 3-(1-menthoxy) propane-1,2-diol, orethyl 3-(paramenthane-3-carboxamido) acetate.

The sensation flavorant may also function as a breath freshening agent.

The flavorant may be a sialogogue and may be capable of stimulating theflow rate of saliva. In some embodiments, the sialogogue may not haveany taste or aromatic properties and may provide no other sensation inthe mouth other than an increased level of saliva. The saliva stimulantmay be, for example, lactose, anhydrous crystalline maltose, ascorbicacid, or malic acid.

The flavorant may be a sensory modifier. The term “sensory modifier”refers to any material which acts to flavor, enhance, or otherwisemodify a subsequent or simultaneous ingestion experience by ‘priming’the buccal cavity. The sensory modifier may, for example, compriseN-ethyl paramenthane 3-carboxamide.

The sensory modifier may sensorially compliment a subsequent orsimultaneous smoking experience by interacting with the smoke from thesmoking article. Such sensory modifiers may, for example, includeglycerol, triacetin, propylene glycol or one or more long chain fattyacid.

In embodiments in which at least two of the populations of particleshave different mean particle sizes, the first population of particles(having a smaller mean particle size) may comprise a stimulant, and thesecond population of particles (having a larger mean particle size) maycomprise a flavorant. In this way, the stimulant may be perceivedquickly by the user and take effect rapidly, whereas the flavorant maybe perceived later and persist for a longer duration.

Enhancer

The powder may comprise a population of particles comprising anenhancer.

The term “enhancer” refers to materials which are capable of improvingthe delivery of the powder or a component of the powder to the user.

The enhancer may comprise a bioadhesive. The terms “bioadhesive” and“bioadhesion” refer to the state in which two materials, at least onebiological in nature, are held together for an extended period of time.Thus, in this case, the inclusion of a bioadhesive may improve thebioavailability of components of the powder. Suitable bioadhesivesinclude polyethylene glycol, polyvinyl alcohol, polyvinyl pyrrolidone,polyacrylic acid, polyhydroxyethyl methacrylate, and chitosan.

The bioadhesive may be a mucoadhesive. Mucoadhesives may be included inthe powder to enable prolonged retention at the buccal mucosal surfaces.Mucoadhesives may have numerous hydrophilic groups, such as hydroxyl,carboxyl, amide, and sulfate, which attach to mucus or the cell membraneby various interactions such as hydrogen bonding and hydrophobic orelectrostatic interactions. Suitable mucoadhesives include lectins andthiolated polymers.

The enhancer may comprise a pH modifier. Substances which modify the pHof particles within the powder may increase the pH of the oral cavity.The resting pH of the oral cavity is typically slightly acidic(6.4-6.9), and providing a powder comprising particles which increasethe pH of the oral cavity can aid transmucosal uptake. Thus, in order toaccelerate or reduce the rate of perception of a sensation, the powdermay include a pH modifier such as sodium carbonate, sodium hydroxide,sodium silicate, sodium phosphates, lime, phosphoric acid, polyphosphoric acid, citric acid, potassium sorbate, poly ethylene imine(PEI).

The enhancer may comprise a substance capable of modifying theelectrostatic charge of particles. Such substances may be included inorder to modify the flow of particles within the powder. Chargedparticles tend to adhere to the walls of the device from which thepowder is to be delivered, which can adversely affect the accuracy ofthe delivered dose. Modification of the electrostatic charge ofparticles within the powder, typically so that the particles repel eachother, can help to prevent such adherence. Use of particular processingparameters for production of the particles can help achieve this aim.Alternatively, or in addition, one or more substances can be included inthe powder which modify the electrostatic charge of the particles. Forexample, the powder may comprise one or more electrets.

The enhancer may comprise a hydrophobic material. Hydrophobic materialscan improve mouth feel and minimize water absorption by the particlesprior to use, thereby extending shelf-life, and/or extending the timeover which the user perceives the sensory experiences imparted by thepowder. Suitable hydrophobic materials include waxes, fatty acids orsalts thereof; monoglycerides, diglycerides or triglycerides; glycerylbehenate, hydrogenated vegetable oil, stearic acid, glycerylmonostearate, glycerylpalmito stearate or cetyl alcohol.

Excipient

The powder may comprise particles of one or more excipient. The term“excipient” refers to a substantially inert material. Such materials aretypically used as, for example, bulking agents, taste regulators, and/orto enhance palatability.

In addition, the presence of an excipient within the powder cancontribute to, and improve, the delivery of the powder to the buccalcavity of a user. Particles within powders tend to agglomerate, andadhere to surfaces within the device which is intended to deliver thepowder to the user. Small particles (less than 50 μm) in particular maybe thermodynamically unstable due to their high surface area to volumeratio. This provides excess surface free energy and encourages particlesto agglomerate. Agglomeration of particles and adherence of particles tothe surfaces of the device can result in the particles leaving thedevice as large stable agglomerates or being unable to leave the deviceand remaining adhered to the interior of the device. Uncertainty as tothe extent of formation of stable agglomerates of the particles betweeneach actuation of the device can lead to reduced powder delivery and/orpoor dose reproducibility. Inclusion of excipient particles can decreaseagglomeration and adherence of particles within the powder to surfaceswithin the device, thus improving powder flow.

Examples of suitable excipients include sugar, starch, lactose, acacia,sodium alginate, carbomer, sodium carbonate, calcium phosphate orcalcium carbonate, cellulose, ethyl cellulose, methyl cellulose andpovidone.

The excipient material may be purchased from a supplier, for exampleMeggle®. The excipient material may be purchased in the form ofparticulate material, with particles within the desired size range.Alternatively, the purchased excipient material may be processed, forexample to break down agglomerates and/or reduce particle size to giveparticles in the desired size range. The excipient particles may then beclassified by size, for example by sieving, and the desired particlesize fraction selected.

The powder may comprise excipient material in the form of a populationof excipient particles. Such a population may comprise up to 99% byweight of the total powder. For example, the excipient particlepopulation may comprise up to 20%, up to 30%, up to 40%, up to 50%, upto 60%, up to 70%, up to 80%, up to 90%, up to 95%, or up to 98% byweight of the total powder.

In addition, or alternatively, the powder may comprise a population ofcomposite particles, wherein each composite particle comprises aplurality of materials that are irreversibly bound together to form asingle particle. In this case, the composite particles may comprise acombination of excipient material and one or more other materials suchas a flavorant, stimulant, and/or enhancer.

Particle Composition

The disclosed powder comprises at least two different populations ofparticles. The terms “population of particles”, “particle population”,and similar expressions refer to a plurality of particles having thesame or substantially the same characteristics. For example, theparticles within a single population have the same, or substantially thesame, size, shape, composition, etc, within a limited range, forexample, differing from the mean value by less than 5%, 2%, or 1%.

The powder may comprise a population of particles wherein each particleis composed of a single material. For example, each particle of thepopulation may simply comprise particles of a flavorant or particles ofa stimulant.

Alternatively, each particle within a population may have a more complexstructure and/or may be composed of a plurality of materials.

For example, each particle within the population may comprise a layeredcomposition, wherein the particle comprises an inner core and an outercoating. In this case, the core may comprise excipient material and thecoating may comprise a flavorant and/or stimulant.

When the particle population comprises an enhancer, this may generallybe present in an outer layer. Thus, each particle in a population maycomprise a core comprising a flavorant or stimulant, and a coatingcomprising an enhancer.

In some embodiments, each particle within the population may comprisethree or more materials, such as four, five, or six materials. Forexample, each particle within a population may have a multi-layeredcomposition and may comprise a core comprising excipient material, anintermediate layer comprising a flavorant and/or stimulant, and an outercoating comprising an enhancer.

When the particle population comprises two or more flavorant,stimulants, and/or enhancers, these may be provided in the form ofdifferent layers. Alternatively, a single layer may comprise a mixtureof two or more different materials such as flavorants.

Each layer or coating may be complete, that is, it may encompass theentire particle. Alternatively, the layer or coating may be incomplete,that is, it may only partially cover the particle.

By means of the use of layering in this way, a population of particlesmay be produced which provides more than one sensory experience to theuser, wherein each sensory experience may be perceived sequentially. Theuse of multiple layers may also extend the time over which the userperceives a sensory experience.

In some embodiments, the powder comprises particles having one or moredistinct shapes. The shape of the particles may, for example, affect themouth feel experienced by the user, and/or the rate of dissolution ofthe particles in the buccal cavity. The powder may, for instance,comprise particles in the form of flakes, particles which aresubstantially spherical, and/or particles which are substantiallyrectilinear.

Different particle shapes may be achieved by means of differentprocessing methods, for example, substantially spherical particles maybe produced by spray drying.

Powder Properties

The powder may be a free-flowing powder in order that it can be readilyentrained in a fluid flow for inhalation.

In some embodiments, the powder may comprise less than about 50 wt %, 40wt %, 30 wt %, 25 wt %, 20 wt %, 15 wt %, 10 wt %, 5 wt %, 4 wt %, 3 wt%, 2 wt % or 1 wt % moisture (on a wet weight basis). High moisturelevels can cause powders to agglomerate, which can reduce the amount ofpowder entrained in a fluid flow in use. Dry, free flowing powders aremore readily entrained in a fluid flow in use, increasing the totalparticulate matter per puff.

Method of Production

In a second aspect, there is provided a method of making a powderaccording to the first aspect, as described above.

Generally, methods involve separately producing at least two differentparticle populations and then mixing them to form the disclosed powder.Mixing is generally performed using a relatively gentle mixing method,such as by means of a rotary mixer or a tumbler mixer.

Various suitable methods of producing particulate material will be knownto the skilled person. For example, one method may involve wet mixingthe ingredients using a high-shear granulator or simple planetary mixer;extruding the resultant mixture; spheronizing the extrudates; andfinally drying the resultant particles, for example in a vertical fluidbed drier.

Another method may simply involve producing one or more large solidmasses of the desired material; pulverizing the one or more masses; andsize classifying the resultant particulate matter to obtain particles ofthe desired size.

Some approaches may involve creating particulate material by drying asolution or suspension. Any means of drying the solution or suspensionwhich gives rise to a particulate material may be used. For example, thesolution or suspension may be dried using means such as spray-drying,drum drying, freeze drying, crystallization, pulse-combination drying,dielectric or microwave drying or use of a fluid bed granulator.

The resultant particles may then be provided with a coating, asdiscussed above. The coating may be applied to the particles byspraying, dipping, or any other method of applying a coating. Forexample, a solution(s) of the constituent(s) to be coated onto theparticles may be prepared, and then applied to the particles usingfluidized bed coating; top or bottom spray coating; pan coating;air-suspension coating; or vapor coating.

In some embodiments, the particles may undergo a deagglomeration step inorder to break down agglomerated particles. The deagglomeration step mayinvolve mechanically breaking up agglomerates, for example by sieving orvibration of the particles.

Resultant particles may then be classified by size, for example bysieving, and the desired particle size fraction selected.

Tobacco Extract

As described above, the flavorant and/or stimulant may be provided inthe form of a tobacco extract.

The tobacco extract may be made by any suitable method. For example, WO2014/020337, the entirety of which is hereby expressly incorporated byreference, discloses an example of a tobacco extract which may be usedin the disclosed powders.

As disclosed in WO 2014/020337, raw tobacco material may be combinedwith water in a mixer, such as a ploughshare or drum mixer, and stirredat about 50 revolutions per minute (rpm) for about 1 hour at a definedtemperature, which may be selected to minimize the loss of aromaticcomponents and/or volatile aromatic compounds, such as nicotine, fromthe mixture. Accordingly, the mixing step may be carried out at or belowambient temperature (considered to be 18-25° C.). The pH of the mixturemay be adjusted prior to, during and/or after the process of theproduction of tobacco extract, to about pH 5.5.

During and/or after the mixing of the tobacco material and water, thesolid and liquid components of the mixture may be separated by anysuitable apparatus, such as a hydropress, one or more centrifugationstep(s) and/or a belt press.

The tobacco extract may then undergo treatment to remove microbes, forexample by membrane filtration, in order to enhance safety in use.

Powder Delivery/Inhaler Device

The disclosure provides an inhaler device containing a powder asdescribed herein. The inhaler device may comprise a housing and a powderchamber within the housing. The powder chamber may be a cartridge whichis retained in the housing in use, the cartridge containing the powder.The cartridge may be removable, allowing the cartridge to be rechargedor replaced once the power has been at least partially consumed. In someembodiments, the cartridge may be retained in the housing by anysuitable means, such as magnetic retention. The cartridge may beretained by a screw-fit, snap-fit or bayonet-fit into the housing.

In some embodiments, the disclosure provides a cartridge containing apowder as described herein, wherein the cartridge is for use in aninhaler device as described herein. In some cases, the cartridge isadapted to be placed in an inhaler device as described herein. Thecartridge may be formed using a rigid materials such as a plastics ormetal material.

In some embodiments, the inhaler device may comprise a closuremechanism. This mechanism is moveable between an open configuration anda closed configuration. In the closed configuration, powder cannot exitthe device. The device must be placed in the open configuration in useto allow inhalation. In some embodiments, the closure mechanism maycomprise a cap or lid.

In use, the powder may be entrained in a fluid flow to create an aerosolwhich is then inhaled. The fluid is typically a gas, suitably air. Insome embodiments, the powder is entrained in air which is drawn throughthe device by the user inhaling.

In some embodiments, the inhaler device may be puff actuated. In suchembodiments, the device may comprise a housing which defines a fluidflow path, the path extending from an inlet provided in the housing,through a powder chamber within the housing and to an outlet from thehousing. In use, the user draws air through the fluid flow path byinhaling through the flow outlet (i.e. at the downstream end of the flowpath). As the air passes through the powder chamber, powder is entrainedin the air flow and exits the housing at the outlet (and is thusdelivered to the user).

In some embodiments, at least one one-way valve may be provided in thefluid flow path, the valve(s) being orientated such that in use, powdermay only exit the housing through the outlet. The valve is biased to aclosed position in the absence of a fluid flow. This arrangementminimizes or prevents powder loss through the fluid flow inlet (causedby a fluid flow in the wrong direction).

In some embodiments, one-way valves may be provided both upstream anddownstream of the powder chamber, the valves being biased to a closedposition in the absence of a fluid flow. The valves are directed toallow fluid flow from the inlet to the outlet only. This means thatpowder cannot exit the powder chamber without a fluid flow beingpresent, minimizing or preventing loss of the powder when the device isnot in use.

In alternative embodiments, the fluid flow may be created by an aerosolgenerating means, such as a propellant, located in the inhaler device.

In some other embodiments, the device may be push-button actuated. Insome embodiments, the device may comprise aerosol generating means,wherein the powder may be entrained in a fluid flow created by theaerosol generating means. In such embodiments, the aerosol generatingmeans may comprise an aerosol generating material or propellant whichmay be retained in a chamber in the inhaler device, and released byactuation of a push-button by the user.

The disclosed powders are typically delivered to the buccal cavity asone or more shots or doses. Several shots of powder may be consumed ineach session of powder usage. Each shot may contain up to about 10 g ofpowder, such as up to about 5, 3, 2, or 1 g. Generally, each shotcontains up to about 500 mg, such as between about 5-450 mg, 10-400 mg,50-375 mg; between 100-350 mg or around 10, 20, 50, 75, 100, 150, 200,250, 275, 300, 325, 350, 375, 400, 425, 450 or 475 mg. Generally, theamount of powder delivered per shot must be sufficient for thesensations provided by the powder populations to be perceived by theuser.

EXAMPLES

A powder was produced comprising two populations of particles. Particlesof the first population were prepared from a tobacco extract, containinga plurality of alkaloid stimulants including nicotine. Particles of thesecond population contained a flavorant in the form of mint oil.

Preparation of Tobacco Extract

12 kg of de-ionized water was added to 8 kg of tobacco material in aWinkworth RT200 mixer and the mixture was stirred at 50 rpm for 60minutes. The solid and liquid components of the mixture were separatedusing a Vigo hydropress, producing raw tobacco extract and a solidextract which was discarded. All of the steps of the production of theextract were carried out at 25° C.

Treatment of Tobacco Extract to Reduce Microbial Content

6 liters of the raw tobacco extract was passed through a sieve with amesh size of 25 μm. The filtrate was centrifuged at 8000 rpm for 10minutes using a Beckman Avanti J-20XP centrifuge at 4° C. The liquidphase was passed through a membrane with a pore size of 10 μm (MilliporeIsopore® membrane, catalogue no. TCTP04700). The filtrate was passedthrough a membrane with a pore size of 5 μm (Millipore Isopore®membrane, catalogue no. TMTP04700). The filtrate was centrifuged at 8000rpm for 10 minutes using a Beckman Avanti J-20XP centrifuge at 4° C. Theliquid phase was passed through a membrane with a pore size of 1.2 μm(Millipore Isopore® membrane, catalogue no. RTTP04700), the filtrate wascentrifuged at 8000 rpm for 10 minutes using a Beckman Avanti J-20XPcentrifuge at 4° C. and the liquid phase was passed through a membranewith a pore size of 0.45 μm (Whatman® cellulose acetate 47 mm membrane,catalogue no. 7000 0004). The filtrate from this microfiltration stepwas then passed through a membrane with a pore size of 0.2 μm (Whatman®cellulose acetate 47 mm membrane, catalogue no. 7001 0004). Unlessstated otherwise, the steps of the extract treatment process werecarried out at 25° C.

Nicotine Content of Tobacco Extract

The nicotine content of the extract was determined according to a methodbased on Canadian official method T-301, “Determination of Alkaloids inWhole Tobacco”. The method was carried out three times and the averagenicotine content was found to be 20.06 mg/mL.

Preparation of Particulate Material from Tobacco Extract

The tobacco extract was then spray dried to produce particulatematerial.

The resultant particles were then sieved using a 10 μm mesh sievefollowed by a 150 μm mesh sieve. The particles that were retained afterthe first sieving step, but that passed through the sieve following thesecond sieving step were selected.

Production of Mint Particles

About 500 ml of boiling water was added to about 250 g of crushed mintleaves. After the mixture had been allowed to steep for 24 hours themixture was strained and the solids discarded.

To the liquid was added the beaten white of an egg and about 900 g ofsugar. The mixture was boiled slowly until thick.

Pellets were produced by dropping small spoonfuls of the mixture intocold water. When cold and dry the pellets were crushed. The resultantparticles were sieved using first a 450 μm mesh sieve and then a 700 μmmesh sieve. The particles that were retained after the first sievingstep, but that passed through the sieve following the second sievingstep were selected.

Production of Powder

To produce the final powder, particles of the first particle population(comprising a tobacco extract), and second particle population(comprising mint particles), were mixed together using a Turbula mixerat 40 rpm for 2 hrs.

The ratio in which the two populations of particles were mixed was suchthat approximately 500 mg of the final powder contained about 1 mg ofnicotine.

The various embodiments described herein are presented only to assist inunderstanding and teaching the claimed features. These embodiments areprovided as a representative sample of embodiments only, and are notexhaustive and/or exclusive. It is to be understood that advantages,embodiments, examples, functions, features, structures, and/or otheraspects described herein are not to be considered limitations on thescope of the invention as defined by the claims or limitations onequivalents to the claims, and that other embodiments may be utilizedand modifications may be made without departing from the scope of theclaimed invention. Various embodiments of the invention may suitablycomprise, consist of, or consist essentially of, appropriatecombinations of the disclosed elements, components, features, parts,steps, means, etc, other than those specifically described herein. Inaddition, this disclosure may include other inventions not presentlyclaimed, but which may be claimed in future.

The invention claimed is:
 1. An inhaler device containing a powder fordelivery to the oral cavity of a user, the powder comprising at leasttwo different populations of particles, wherein a first population ofparticles has a mean particle size of 7 μm-350 μm and comprises astimulant comprising nicotine, and a second population of particles hasa mean particle size of 350 μm-750 μm and comprises a flavorant, orwherein a first population of particles has a mean particle size of 350μm-750 μm and comprises a stimulant comprising nicotine, and a secondpopulation of particles has a mean particle size of 7 μm-350 μm andcomprises a flavorant, and wherein the powder does not comprise apopulation of particles that consists only of sugar.
 2. The inhalerdevice according to claim 1, wherein the powder consists of three, four,five, or six populations of particles.
 3. The inhaler device accordingto claim 1, wherein the stimulant sensation provided by the firstpopulation of particles demonstrates a different rate of at least one ofperception or duration compared to the flavorant sensation provided bythe second population of particles.
 4. The inhaler device according toclaim 1, wherein the mean particle size of the first population ofparticles is less than 50% or greater than 100% of the mean particlesize of the second population of particles.
 5. The inhaler deviceaccording to claim 1, wherein nicotine is an extract from tobacco. 6.The inhaler device according to claim 1, wherein the stimulant furthercomprises caffeine, theophylline, or theobromine.
 7. The inhaler deviceaccording to claim 1, wherein the flavorant comprises at least one fromthe group consisting of a sugar substitute, a sensation flavorant, asaliva stimulant, and a sensory modifier.
 8. The inhaler deviceaccording to claim 1, wherein at least one of the at least two differentpopulations of particles further comprises at least one of an enhancercomprising a bioadhesive, a pH modifier, or a hydrophobic material. 9.The inhaler device according to claim 1, wherein at least one of the atleast two different populations of particles is composite particlescomprising an internal core and an external coating.
 10. The inhalerdevice according to claim 9, wherein the coating comprises the stimulantor flavorant.
 11. The inhaler device of claim 1, further comprising acartridge containing the powder.
 12. The inhaler device according toclaim 1, wherein the mean particle size of the first population ofparticles is 10 μm-350 μm and the mean particular size of the secondpopulation of particles is 350 μm-750 μm, or the mean particle size ofthe second population of particles is 10 μm-350 μm and the mean particlesize of the first population of particles is 350 μm-750 μm.
 13. Theinhaler device according to claim 12, wherein the mean particle size ofthe first population of particles is 10 μm-150 μm and the mean particlesize of the second population of particles is 350 μm-750 μm, or the meanparticle size of the second population of particles is 10 μm-150 μm andthe mean particle size of the first population of particles is 350μm-750 μm.
 14. The inhaler device according to claim 1, wherein the meanparticle size of the first population of particles is 10 μm-350 μm andthe mean particle size of the second population of particles is 450μm-750 μm, or the mean particle size of the second population ofparticles is 10 μm-350 μm and the mean particle size of the firstpopulation of particles is 450 μm-750 μm.
 15. The inhaler deviceaccording to claim 1, wherein at least one of the first population ofparticles or the second population of particles further comprises one ormore electrets.